The Status and Impact of Clinical Tumor Genome Sequencing

2019 ◽  
Vol 20 (1) ◽  
pp. 413-432 ◽  
Author(s):  
Kenna R. Mills Shaw ◽  
Anirban Maitra
Keyword(s):  
Genome Sequencing ◽  
Large Scale ◽  
Turnaround Time ◽  
Tumor Type ◽  
Sequencing Technologies ◽  
Pristine Sample ◽  
Specific Tumor ◽  
The Status ◽  
Dna Alterations ◽  
Tumor Genome

Since the discovery that DNA alterations initiate tumorigenesis, scientists and clinicians have been exploring ways to counter these changes with targeted therapeutics. The sequencing of tumor DNA was initially limited to highly actionable hot spots—areas of the genome that are frequently altered and have an approved matched therapy in a specific tumor type. Large-scale genome sequencing programs quickly developed technological improvements that enabled the deployment of whole-exome and whole-genome sequencing technologies at scale for pristine sample materials in research environments. However, the turning point for precision medicine in oncology was the innovations in clinical laboratories that improved turnaround time, depth of coverage, and the ability to reliably sequence archived, clinically available samples. Today, tumor genome sequencing no longer suffers from significant technical or financial hurdles, and the next opportunity for improvement lies in the optimal utilization of the technologies and data for many different tumor types.

scholarly journals Multi-platform discovery of haplotype-resolved structural variation in human genomes

2017 ◽  
Author(s):  
Mark J.P. Chaisson ◽  
Ashley D. Sanders ◽  
Xuefang Zhao ◽  
Ankit Malhotra ◽  
David Porubsky ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Large Scale ◽  
Structural Variation ◽  
High Throughput Sequencing ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Full Spectrum ◽  
Variant Discovery ◽  
Sequencing Technologies ◽  
Sequencing Studies

ABSTRACTThe incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, and strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three human parent–child trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per human genome. We also discover 156 inversions per genome—most of which previously escaped detection. Fifty-eight of the inversions we discovered intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The method and the dataset serve as a gold standard for the scientific community and we make specific recommendations for maximizing structural variation sensitivity for future large-scale genome sequencing studies.

scholarly journals Discovery of photosynthesis genes through whole-genome sequencing of acetate-requiring mutants of Chlamydomonas reinhardtii

PLoS Genetics ◽  
2021 ◽  
Vol 17 (9) ◽  
pp. e1009725
Author(s):  
Setsuko Wakao ◽  
Patrick M. Shih ◽  
Katharine Guan ◽  
Wendy Schackwitz ◽  
Joshua Ye ◽  
...  
Keyword(s):  
Chlamydomonas Reinhardtii ◽  
Candidate Genes ◽  
Genome Sequencing ◽  
Large Scale ◽  
Insertional Mutagenesis ◽  
Functional Annotations ◽  
Sequencing Technologies ◽  
Tetrapyrrole Synthesis ◽  
Conserved Genes ◽  
Photosynthesis Genes

Large-scale mutant libraries have been indispensable for genetic studies, and the development of next-generation genome sequencing technologies has greatly advanced efforts to analyze mutants. In this work, we sequenced the genomes of 660 Chlamydomonas reinhardtii acetate-requiring mutants, part of a larger photosynthesis mutant collection previously generated by insertional mutagenesis with a linearized plasmid. We identified 554 insertion events from 509 mutants by mapping the plasmid insertion sites through paired-end sequences, in which one end aligned to the plasmid and the other to a chromosomal location. Nearly all (96%) of the events were associated with deletions, duplications, or more complex rearrangements of genomic DNA at the sites of plasmid insertion, and together with deletions that were unassociated with a plasmid insertion, 1470 genes were identified to be affected. Functional annotations of these genes were enriched in those related to photosynthesis, signaling, and tetrapyrrole synthesis as would be expected from a library enriched for photosynthesis mutants. Systematic manual analysis of the disrupted genes for each mutant generated a list of 253 higher-confidence candidate photosynthesis genes, and we experimentally validated two genes that are essential for photoautotrophic growth, CrLPA3 and CrPSBP4. The inventory of candidate genes includes 53 genes from a phylogenomically defined set of conserved genes in green algae and plants. Altogether, 70 candidate genes encode proteins with previously characterized functions in photosynthesis in Chlamydomonas, land plants, and/or cyanobacteria, 14 genes encode proteins previously shown to have functions unrelated to photosynthesis. Among the remaining 169 uncharacterized genes, 38 genes encode proteins without any functional annotation, signifying that our results connect a function related to photosynthesis to these previously unknown proteins. This mutant library, with genome sequences that reveal the molecular extent of the chromosomal lesions and resulting higher-confidence candidate genes, will aid in advancing gene discovery and protein functional analysis in photosynthesis.

scholarly journals Discovery of photosynthesis genes through whole-genome sequencing of acetate-requiring mutants of Chlamydomonas reinhardtii

2021 ◽  
Author(s):  
Setsuko Wakao ◽  
Patrick M. Shih ◽  
Katharine Guan ◽  
Wendy Schackwitz ◽  
Joshua Ye ◽  
...  
Keyword(s):  
Chlamydomonas Reinhardtii ◽  
Candidate Genes ◽  
Genome Sequencing ◽  
Large Scale ◽  
Insertional Mutagenesis ◽  
Functional Annotations ◽  
Sequencing Technologies ◽  
Tetrapyrrole Synthesis ◽  
Conserved Genes ◽  
Photosynthesis Genes

AbstractLarge-scale mutant libraries have been indispensable for genetic studies, and the development of next-generation genome sequencing technologies has greatly advanced efforts to analyze mutants. In this work, we sequenced the genomes of 660 Chlamydomonas reinhardtii acetate-requiring mutants, part of a larger photosynthesis mutant collection previously generated by insertional mutagenesis with a linearized plasmid. We identified 554 insertion events from 509 mutants by mapping the plasmid insertion sites through paired-end sequences, in which one end aligned to the plasmid and the other to a chromosomal location. Nearly all (96%) of the events were associated with deletions, duplications, or more complex rearrangements of genomic DNA at the sites of plasmid insertion, and 1405 genes in total were affected. Functional annotations of these genes were enriched in those related to photosynthesis, signaling, and tetrapyrrole synthesis as would be expected from a library enriched for photosynthesis mutants. Systematic manual analysis of the disrupted genes for each mutant generated a list of 273 higher-confidence candidate photosynthesis genes, and we experimentally validated two genes that are essential for photoautotrophic growth, CrLPA3 and CrPSBP4. The inventory of candidate genes includes 55 genes from a phylogenomically defined set of conserved genes in green algae and plants. Altogether, 68 candidate genes encode proteins with previously characterized functions in photosynthesis in Chlamydomonas, land plants, and/or cyanobacteria, 15 genes encode proteins previously shown to have functions unrelated to photosynthesis, and 190 genes encode proteins without any functional annotation, signifying that our results connect a function related to photosynthesis to these previously unknown proteins. This mutant library, with genome sequences that reveal the molecular extent of the chromosomal lesions and resulting higher-confidence candidate genes, represents a rich resource for gene discovery and protein functional analysis in photosynthesis.

0306 Exploring the feasibility of using copy number variants as genetic markers through large-scale whole genome sequencing experiments

2016 ◽  
Vol 94 (suppl_5) ◽  
pp. 146-146
Author(s):  
D. M. Bickhart ◽  
L. Xu ◽  
J. L. Hutchison ◽  
J. B. Cole ◽  
D. J. Null ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genetic Markers ◽  
Genome Sequencing ◽  
Copy Number ◽  
Large Scale ◽  
Copy Number Variants ◽  
Whole Genome

scholarly journals Nebula: ultra-efficient mapping-free structural variant genotyper

2021 ◽  
Author(s):  
Parsoa Khorsand ◽  
Fereydoun Hormozdiari
Keyword(s):  
Large Scale ◽  
Structural Variants ◽  
Sequencing Technologies ◽  
Generic Framework ◽  
Common Genetic Variants ◽  
Order Of Magnitude ◽  
Complex Events ◽  
Comparable Accuracy ◽  
Using Data ◽  
Computational Resources

Abstract Large scale catalogs of common genetic variants (including indels and structural variants) are being created using data from second and third generation whole-genome sequencing technologies. However, the genotyping of these variants in newly sequenced samples is a nontrivial task that requires extensive computational resources. Furthermore, current approaches are mostly limited to only specific types of variants and are generally prone to various errors and ambiguities when genotyping complex events. We are proposing an ultra-efficient approach for genotyping any type of structural variation that is not limited by the shortcomings and complexities of current mapping-based approaches. Our method Nebula utilizes the changes in the count of k-mers to predict the genotype of structural variants. We have shown that not only Nebula is an order of magnitude faster than mapping based approaches for genotyping structural variants, but also has comparable accuracy to state-of-the-art approaches. Furthermore, Nebula is a generic framework not limited to any specific type of event. Nebula is publicly available at https://github.com/Parsoa/Nebula.

Microcomputers in Political Science

1983 ◽  
Vol 38 ◽  
pp. 1-9
Author(s):  
Herbert F. Weisberg
Keyword(s):  
Data Analysis ◽  
Political Science ◽  
Large Scale ◽  
Turnaround Time ◽  
General Purpose ◽  
Batch Mode ◽  
New Era ◽  
Large Scale Data ◽  
The Social ◽  
Frequency Counts

We are now entering a new era of computing in political science. The first era was marked by punched-card technology. Initially, the most sophisticated analyses possible were frequency counts and tables produced on a counter-sorter, a machine that specialized in chewing up data cards. By the early 1960s, batch processing on large mainframe computers became the predominant mode of data analysis, with turnaround time of up to a week. By the late 1960s, turnaround time was cut down to a matter of a few minutes and OSIRIS and then SPSS (and more recently SAS) were developed as general-purpose data analysis packages for the social sciences. Even today, use of these packages in batch mode remains one of the most efficient means of processing large-scale data analysis.

scholarly journals The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy

2021 ◽  
Vol 22 (2) ◽  
pp. 603
Author(s):  
Manlio Tolomeo ◽  
Antonio Cascio
Keyword(s):  
Tumor Promoter ◽  
Tumor Type ◽  
Signal Transducer ◽  
Suppressor Factor ◽  
Specific Tumor ◽  
Cytokine Stimulation ◽  
Pleiotropic Functions ◽  
Stat3 Mutations ◽  
Potent Tumor

Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type.

An Optimized Method for the Preparation of Monascus purpureus DNA for Genome Sequencing

2014 ◽  
Vol 563 ◽  
pp. 379-383 ◽  
Author(s):  
Yue Yang ◽  
Xin Jun Du ◽  
Ping Li ◽  
Bin Liang ◽  
Shuo Wang
Keyword(s):  
Genome Sequencing ◽  
Genomic Dna ◽  
Benzyl Chloride ◽  
Monascus Purpureus ◽  
Sequencing Technologies ◽  
Fungal Evolution ◽  
Ctab Method ◽  
Fungal Dna ◽  
Gene Functional Analysis ◽  
Generation Sequencing

More and more attention has been paid to filamentous fungal evolution, metabolic pathway and gene functional analysis via genome sequencing. However, the published methods for the extraction of fungal genomic DNA were usually costly or inefficient. In the present study, we compared five different DNA extraction protocols: CTAB protocol with some modifications, benzyl chloride protocol with some modifications, snailase protocol, SDS protocol and extraction with the E.Z.N.A. Fungal DNA Maxi Kit (Omega Bio-Tek, USA). The CTAB method which we established with some modification in several steps is not only economical and convenient, but also can be reliably used to obtain large amounts of highly pure genomic DNA fromMonascus purpureusfor sequencing with next-generation sequencing technologies (Illumina and 454) successfully.

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